CN1505510A - Medicine combinations using pyridoindolone derivatives and anticancer agent as base - Google Patents

Medicine combinations using pyridoindolone derivatives and anticancer agent as base Download PDF

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CN1505510A
CN1505510A CNA028088980A CN02808898A CN1505510A CN 1505510 A CN1505510 A CN 1505510A CN A028088980 A CNA028088980 A CN A028088980A CN 02808898 A CN02808898 A CN 02808898A CN 1505510 A CN1505510 A CN 1505510A
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methyl
hydrogen atom
represent hydrogen
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ethyl
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CN1240382C (en
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B
B·布里
P·卡塞拉斯
J·－M·德罗克
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Sanofi Aventis France
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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Abstract

The invention concerns the combination of compounds of formula (I) with several anticancer agents.

Description

With pyrido indolone derivatives and anticarcinogen is the drug regimen of base
The objective of the invention is the new combination (association) of pyrido indolone derivatives and anticarcinogen and contain their pharmaceutical composition.
Spendable pyrido indolone derivatives is a following formula: compound among the present invention:
Figure A0280889800051
In the formula:
-R 1Represent hydrogen atom or methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-r 3Representative or the phenyl that is randomly replaced, perhaps thienyl by halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
Once discoverable type (I) chemical compound, i.e. anticarcinogen can be advantageously and other anticarcinogen combination.
Preferred pyrido indolone derivatives is a following formula: compound:
Figure A0280889800052
In the formula:
-R 1Represent hydrogen atom, methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-R 3Represent hydrogen atom or halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
The derivant of particularly preferred pyrido indolone is the chemical compound of following formula:
Figure A0280889800061
Wherein:
-R 1Represent hydrogen atom, methyl or ethyl;
-R 2Represent methylidene or ethyl;
-R 3Represent hydrogen atom or halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
The derivant of more preferred pyrido indolone is a following formula: compound:
In the formula:
-R 1Represent methylidene or ethyl;
-R 2Represent methylidene or ethyl;
-R 3Represent hydrogen atom or halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
As an example, pyrido indolone derivatives of the present invention is:
6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
F＝178.5-179.5℃；
3-(4-methoxyphenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
F＝166-167℃；
1,6,9-trimethyl-3-(3-thienyl)-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
RMN(200MHz)：2.6ppm∶s∶3H；4.1ppm∶s∶3H；4.2ppm∶s∶3H；7.1ppm∶d∶1H；7.4-7.9ppm∶m∶4H；8.3ppm∶d∶1H；8.7ppm∶s∶1H。
1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
F＝198-199℃；
1,6-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
RMN(200MHz)：2.5ppm∶s∶3H；3.8ppm∶s∶3H；7.1ppm∶d∶1H；7.3-7.5ppm∶m∶4H；7.75ppm∶d∶2H；7.8ppm∶s∶1H；8.4ppm∶s∶1H；11.8ppm∶s∶1H。
According to method preparation formula (I) chemical compound of describing among the file FR 97 08409.
In vitro formula (I) chemical compound is crossed in vitro tests to the human breast cancerous cell line: from the obtainable cell line MDA-MB-231 of American type culture collection (preserving number HTB26).
According to people such as J.M.Derocq, FEBS Letters, 1998,425, the 419-425 page or leaf has carried out the evaluation of antiproliferative effect: with formula (I) chemical compound incubation 96 hours after, be determined at [3H] thymidine incorporation efficiency among the DNA that handles cell.50% inhibition concentration (IC 50) be defined as the concentration that suppresses cell proliferation 50%.
These formulas (I) chemical compound is for the IC of MDA-MB-231 cell line 50Be generally less than 10 μ M.
Also to another kind of human breast cancerous cell line, promptly described multiresistance cell line MDR, and be referred to as MDA-A 1, tested formula (I) chemical compound.E.Collomb, C.Dussert and P.M.Martin be at Cytometry, and 1991,12 (1), this cell line was described in the 15-25 page or leaf.
The term " multiresistance " of this cell line is described, the meaning is the anti-mitosis medicine of above-mentioned cell line to normally used chemotherapeutics, particularly natural origin, for example paclitaxel (paclitaxel), in general vincristine, vinblastine are not too responsive.
Formula (I) chemical compound is for multiresistance cell line MDA-A 1IC 50Be generally less than 10 μ M.
Therefore, formula (I) chemical compound suppresses the propagation of tumor cell, comprising the cell proliferation with multiresistance.
Also estimated several formulas (I) chemical compound in vivo according to model to the subcutaneous implantation people tumor xenogeneic graft of mice SCID (is serious merging immunodeficiency from English) of immunocompromised.
Reach about 60 milligram hours of tumor quality and begin usefulness formula (I) compound treatment animal when transplanting the 6-7 days tumors in back.The solution of this chemical compound in solvent is by with the oral route medication.
The average tumor quality reaches about 1000 milligram hours evaluation anti-tumor activity in only with the control animal body of solvent processing: measure the T/C ratio, T represents the average weight of the tumor of the animal of receiving treatment, and C represents the average weight of the tumor of control animal.According to people such as Stuart T, at J.Med.Chem., the description in 2001,44 (11), the 1758-1776 page or leaf, the T/C ratio is less than or equal to 42% and is considered to the active indication of effective antitumor.When day, taking dose was between 50 and 300 mg/kg, some formula (I) chemical compound reached the T/C ratio less than 20%.
According to reference technique (J.M.Derocq etc.), to MDA-A 1Cell line, promptly above-mentioned so-called multiresistance cell line has been measured the antiproliferative effect that formula (I) chemical compound and another kind of anticarcinogen make up.Only with IC that anticarcinogen reached 50With the IC that is reached with identical anticarcinogen and the combination of formula (I) chemical compound 50Compare.Observe IC 50Obviously reduce.For the derivant and the combination of another kind of anticarcinogen of some formula (I) pyrido indolone, can use coefficient 2 to 100, even surpass 100 except that IC 50
As an example, the IC that only reaches with paclitaxel 50With usefulness paclitaxel and 1,6,9-trimethyl-3-phenyl-1, the IC that the combination of 9-dihydro-2H-pyrido [2,3-b] indol-2-one reaches 50Compare.According to 1,6 of use, 9-trimethyl-3-phenyl-1, the concentration of 9-dihydro-2H-pyrido [2,3-b] indol-2-one, IC 50Can be removed 14 to 100 by coefficient.
Result of the test proves that composition of the present invention has the potentiality of cooperative effect and antiproliferative effect.
According to the present invention, can take one or more formulas (I) chemical compound when making up with a kind of (or multiple) anticancer active constituent.These active component especially can be antitumoral compounds, alkylating agent class for example, and alkyl sulfonic ester (1,4-dimethane sulfonoxybutane), dacarbazine, procarbazine contains chlormethine (mustine hydrochlcride, melphalan, chlorambucil), cyclophosphamide, ifosfamide; Nitrosoureas, Carmustine for example, chlorethyl cyclohexyl nitrosourea, CH3-CCNU, streptozotocin; The anti-tumor biological bases, vincristine for example, vinblastine; Taxine kind, for example paclitaxel; Antitumor antibiotics class, for example D actinomycin D; Additive kind, antineoplastic antimetabolite class, folate antagonist, methotrexate; The purine synthetic inhibitor; Purine analogue, purinethol for example, 6-thioguanine; The pyrimidine synthesis inhibitors class, aromatase inhibitor class, cap é citabine, pyrimidine analogue, fluorouracil for example, gemcitabine, cytarabine and arabinose glucosides cytosine; Br é quinar; Anticancer hormone agonist and antagonist class are comprising tamoxifen; The inhibitors of kinases class, imatinib; The growth factor receptor inhibitors class; Some antiinflammatory classes that work in carcinoma field, many sulfate of pentosan for example, corticosteroid, prednisone, dexamethasone; Anti-topoisomerase enzyme, etoposide for example, antracyclines, comprising amycin, bleomycin, mitomycin and m é thramycine; Antitumor metal complex class, platinum complex, cisplatin, carboplatin, oxaliplatin; The interferon-alpha class, triphenyl thio-phosphamide, altretamine; The anti-angiogenic agent class; Immunization therapy adjuvant class.
These combinations of the present invention are for prevention and treatment is caused by tumor cell proliferation or the disease of aggravate is effective, and its disease for example is constitutional or metastatic tumour, malignant tumor and cancer, particularly mastocarcinoma; Pulmonary carcinoma; Carcinoma of small intestine, colon cancer and rectal cancer; Respiratory cancer, oropharynx and swallow cancer; Esophageal carcinoma; Hepatocarcinoma, gastric cancer, cancer of biliary duct, carcinoma of gallbladder, cancer of pancreas; Comprising kidney and urothelium in interior carcinoma of urethra, bladder cancer; The female genital tract cancer, comprising uterus carcinoma, cervical cancer, ovarian cancer, chloriocarcinome, and chorionic epithelioma; Male genetic road cancer, comprising carcinoma of prostate, carcinoma of seminal vesicle, carcinoma of testis, germ cell tumor; Endocrine body of gland cancer, comprising thyroid carcinoma, hypophysis cancer, adrenal carcinoma; Skin carcinoma, comprising hemangioma, melanoma, sarcoma is comprising Kaposi sarcoma; Brain tumor, neural tumor, ocular tumor, meningeal tumor, comprising astrocytoma, glioma, glioblastoma, retinoblastoma, neuroblastoma, schwannoma, acoustic nerve schwannoma, meningioma; The hemopoietic malignant growth is grown tumor, comprising leukemia, and chloroma, plasmocytoma, Zhang shape mycosis, the lymphoma of T cell or leukemia, non-Hodgkin lymphomas, malignant hematologic disease, myeloma.
A further object of the invention is a pharmaceutical composition, they contain at least a formula (I) chemical compound for the treatment of effective dose or the acceptable salt of pharmacy of described chemical compound, hydrate or solvate are as one or more active component, with a kind of (or several) another or multiple anticancer active constituent of treatment effective dose, and the acceptable excipient of one or more pharmacy.
Select described excipient according to the administering mode of pharmaceutical dosage form and hope, comprising conventional excipients known in the prior art.
Can prepare, be used to prevent or treat in oral, the Sublingual of above-mentioned disease, subcutaneous, intramuscular, intravenous, part, local, the trachea, the pharmaceutical composition of the present invention of percutaneous or rectal application, the perhaps pharmaceutical composition of the present invention of any suitable approach medication of other of animal and human.
Can be 0.002 to 2000 milligram daily dose with every kilogram of weight of mammal to be treated, preferably 0.1 to 300 mg/kg daily dose uses the chemical compound of above-mentioned formula (I).On the person, according to person's to be treated age or treatment type (preventative or healing property) change dosage, 0.02 to 10000 milligram of preferred every day, more particularly, 1 to 3000 milligram.
Dosage uses the anticancer active constituent with the chemical compound combination of formula (I) routinely.
Suitable form of administration comprises peroral dosage form, tablet for example, soft capsule or hard capsule, powder, granule and oral administration solution or suspensoid, the Sublingual, the oral cavity is in the trachea, ophthalmic is by sucking intranasal administration dosage form, part, percutaneous, subcutaneous, intramuscular or intravenous administration dosage form, rectally dosage form and implant administration form.For local coating, can use the present invention to make up cream, gel, ointment or lotion.
According to conventional practice, the doctor can be according to administering mode, and described patient's age, body weight and symptom are determined each patient's proper dosage.
According to a further aspect in the invention, during the patient treatment that causes by tumor cell proliferation or increase the weight of, can be simultaneously, successively or by stages mode is used one or more formulas (I) chemical compound and a kind of (or multiple) other anticancer active constituent.
The present invention's combination can be kit form, and described test kit is equipped with chemical compound and a kind of (or several) other anticancer active constituent of at least a formula (I).
According to the another one aspect, the invention still further relates to the treatment of diseases method that is caused or increased the weight of by tumor cell proliferation, this method is to allow chemical compound and a kind of (or multiple) other anticancer active constituent of at least a formula (I) that needs experimenter's administering therapeutic effective dose of treatment.

Claims (6)

1. the combination of at least a following formula: compound and a kind of (or multiple) anticancer active constituent:
In the formula:
-R 1Represent hydrogen atom or methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-r 3Representative or the phenyl that is randomly replaced, perhaps thienyl by halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
2. the combination of at least a following formula: compound according to claim 1:
In the formula:
-R 1Represent hydrogen atom, methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-R 3Represent hydrogen atom or halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
3. according to the combination of claim 1 or the described at least a following formula: compound of claim 2:
Figure A0280889800031
Wherein:
-R 1Represent hydrogen atom, methyl or ethyl;
-R 2Represent methylidene or ethyl;
-R 3Represent hydrogen atom or halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
4. combination according to claim 1, its Chinese style (I) chemical compound is wherein a kind of following chemical compound:
-6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
-3-(4-methoxyphenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
-1,6,9-trimethyl-3-(3-thienyl)-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
-1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
-1,6-dimethyl 3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one.
5. contain and at least a following formula: compound of a kind of (or multiple) anticancer active constituent combination and the pharmaceutical composition of one or more pharmaceutical acceptable excipients:
Figure A0280889800032
In the formula:
-R 1Represent hydrogen atom or methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-r 3Representative or the phenyl that is randomly replaced, perhaps thienyl by halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy.
6. treat the test kit of tumor cell proliferation, it is at least a following formula: compound that this test kit contains some:
Figure A0280889800041
In the formula:
-R 1Represent hydrogen atom or methyl or ethyl;
-R 2Represent methylidene or ethyl; Perhaps
-R 1And R 2Form (CH together 2) 3Group;
-r 3Representative or the phenyl that is randomly replaced, perhaps thienyl by halogen atom or methyl or methoxy;
-R 4Represent hydrogen atom or chlorine atom or methyl or methoxy;
Another part is a kind of (or multiple) anticancer active constituent;
These chemical compounds are contained in the different grid, and are used for simultaneously, successively or mode administration by stages.
CNB028088980A 2001-04-27 2002-04-26 Pharmaceutical composition based on pyridoindolone derivatives and anticancer agents Expired - Fee Related CN1240382C (en)

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FR0105843A FR2823975B1 (en) 2001-04-27 2001-04-27 NEW USE OF PYRIDOINDOLONE

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FR2892416B1 (en) 2005-10-20 2008-06-27 Sanofi Aventis Sa 6-HETEROARYLPYRIDOINDOLONE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF

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CN100537568C (en) * 2004-04-21 2009-09-09 赛诺菲-安万特 6-substituted pyridoindolone derivatives, their preparation and therapeutic use

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